Cockayne syndrome pathogenesis: Lessons from mouse models

Dick Jaarsma, Ingrid van der Pluijm, Gijsbertus T.J. van der Horst, Jan H.J. Hoeijmakers

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)

Abstract

Cockayne syndrome (CS) is a rare multisystem disorder characterized by cachectic dwarfism, nervous system abnormalities and features of premature aging. CS symptoms are associated with mutations in 5 genes, CSA, CSB, XPB, XPD and XPG encoding for proteins involved in the transcription-coupled subpathway of nucleotide excision DNA repair (NER). Mutant mice have been generated for all CS-associated genes and provide tools to examine how the cellular defects translate into CS symptoms. Mice deficient for Csa or Csb genetically mimic CS in man, and develop mild CS symptoms including reduced fat tissue, photoreceptor cell loss, and mild, but characteristic, nervous system pathology. These mild CS models are converted into severe CS models with short life span, progressive nervous system degeneration and cachectic dwarfism after simultaneous complete inactivation of global genome NER. A spectrum of mild-to-severe CS-like symptoms occurs in Xpb, Xpd, and Xpg mice that genetically mimic patients with a disorder that combines CS symptoms with another NER syndrome, xeroderma pigmentosum. In conclusion, CS mouse models mice develop a range of CS phenotypes and open promising perspectives for testing interventional approaches.

Original languageEnglish
Pages (from-to)180-195
Number of pages16
JournalMechanisms of Ageing and Development
Volume134
Issue number5-6
DOIs
Publication statusPublished - May 2013
Externally publishedYes

Keywords

  • Cachexia
  • DNA repair
  • Neuronal degeneration
  • Oligodendrocytes
  • Photoreceptor cells
  • Transcription coupled repair

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